Factors associating with differences in the incidence of renal replacement therapy among elderly : data from the ERA-EDTA Registry

Background. The incidence of renal replacement therapy (RRT) in the general population >= 75 years of age varies considerably between countries and regions in Europe. Our aim was to study characteristics and survival of elderly RRT patients and to find explanations for differences in RRT incidence. Methods. Patients >= 75 years of age at the onset of RRT in 2010-2013 from 29 national or regional registries providing data to the European Renal Association-European Dialysis and Transplant Association Registry were included. Chi-square and Mann-Whitney U tests were used to assess variation in patient characteristics and linear regression was used to study the association between RRT incidence and various factors. Kaplan-Meier curves and Cox regression were employed for survival analyses. Results. The mean annual incidence of RRT in the age group >= 75 years of age ranged from 157 to 924 per million age-related population. The median age at the start of RRT was higher and comorbidities were less common in areas with higher RRT incidence, but overall the association between patient characteristics and RRT incidence was weak. The unadjusted survival was lower in high-incidence areas due to an older age at onset of RRT, but the adjusted survival was similar [relative risk 1.00 (95% confidence interval, 0.97-1.03)] in patients from low- and high-incidence areas. Conclusions. Variation in the incidence of RRT among the elderly across European countries and regions is remarkable and could not be explained by the available data. However, the survival of patients in low-and high-incidence areas was remarkably similar.Peer reviewe

Contribution à l'étude du rôle du récepteur à l'antigène des cellules B dans l'hypermutation somatique et la commutation isotypique

L'hypermutation somatique et la communication isotypique sont deux volets essentiels de la maturation de la réponse immunitaire. De nombreux travaux se sont intéressés à ces processus sous leurs aspects transcriptionnels, notamment aux éléments cis-régulateurs, mais très peu de données concernant l'implication du récepteur à l'antigène des cellules B (BCR) sont aujourd'hui disponibles. Dans une première partie, nous nous sommes intéressés à la capacité d'IgM et d'IgA, de même affinité pour le même antigène, d'induire in vitro l'hypermutation somatique dans la lignée humaine BL2. Nous avons trouvé que les deux isotypes pouvaient induire l'hypermutation mais de manière dose-dépendante. Dans la deuxième partie, nous avons utilisé des BCRs natifs et chimériques pour étudier le rôle des domaines cytoplasmiques des isotypes commutés dans la transduction du signal et la down-modulation. Nous avons trouvé que ces domaines ne traduisaient pas de signal, mais qu'ils assuraient la down-modulation de leur BCR de manière strictement dépendante de la tyrosine conservée dans ces domaines, révélant ainsi un rôle régulateur de cette tyrosine. Dans le but d'évaluer le rôle de l'hétérodimère Ig"/Igb dans la mémoire immunologique, en l'absence totale des domaines cytoplasmiques des isotypes non-IgM/IgD, nous avons cherché à bloquer la commutation isotypique. Nous avons délété, par recombinaison homologue, la majeure partie de l'intron I:-C:. L'analyse des souris obtenues a révélé une sévère diminution de la commutation isotypique, mais pas un blocage complet, avec un décalage significatif des sites donneurs de commutation vers l'exon I:, et une absence quasi-totale des mutations introduites par AIDLIMOGES-BU Sciences (870852109) / SudocSudocFranceF

Internalization and molecular interactions of human CD21 receptor.

International audienceThe human CD21 is a receptor for cleavage fragments of the third complement component and for Epstein-Barr virus. Previous mutational studies showed that the cytoplasmic domain of CD21 is absolutely required for internalization of either ligand. With the exception of CD19, CD81, Leu-13 and CD35 that can form a complex with CD21 at the cell surface, no other partner that interacts with the hCD21 transmembrane or the cytoplasmic domain was identified. We investigated the internalization capacity of hCD21 tail mutants in the absence of B cell receptor cross-linking by using stable murine B cell transfectants. We provide evidence that at least two internalization motifs are activated when hCD21 binds a monoclonal antibody. In order to identify the cellular proteins that interact with the hCD21 transmembrane and cytoplasmic domains, we combined a mutational mapping with a two-hybrid system approach both in yeast and in mammalian cells. We identified four novel partners that are involved in intracellular trafficking, sorting or cytoskeleton remodeling and we mapped the hCD21 transmembrane and tail subdomains they interact with. We discuss the potential physiological significance of these findings in the context of hCD21 internalization and intracellular trafficking

Induction of somatic hypermutation by antigen-specific B cell receptors in the human BL2 cell line.

The role of the B cell antigen receptor in the induction of somatic hypermutation is presently unclear. We established stable transfectants of the human BL2 cell line expressing hen-egg lysozyme-specific IgM or IgA and compared their ability to induce somatic hypermutation of the endogenous rearranged heavy-chain gene. We found that IgM and IgA were both able to induce somatic hypermutation in an antigen dose-independent manner. The mutations displayed most of the characteristics of somatic hypermutation in vivo. Notably, some replacements introduced stop codons in the coding region. Our data suggest that class-switched memory B cells may undergo somatic hypermutation. They also suggest that the transmembrane/cytoplasmic domains of the class-switched isotypes modulate the signaling and down-modulation activities of the BCR in an antigen dose-dependent manner

Immunoglobulin class-switch recombination in mice devoid of any S mu tandem repeat.

Immunoglobulin heavy-chain class-switch recombination (CSR) occurs between highly repetitive switch sequences located upstream of the constant region genes. However, the role of these sequences remains unclear. Mutant mice were generated in which most of the I mu -- C mu intron was deleted, including all the repeats. Late B-cell development was characterized by a severe impairment, but not a complete block, in class switching to all isotypes despite normal germ line transcription. Sequence analysis of the I mu -- C mu intron in in vitro activated-mutant splenocytes did not reveal any significant increase in activation-induced cytidine deaminase (AID)-induced somatic mutations. Analysis of switch junctions showed that, in the absence of any S mu repeat, the Imicro exon was readily used as a substrate for CSR. In contrast to the sequence alterations downstream of the switch junctions, very few, if any, mutations were found upstream of the junction sites. Our data suggest that the core E mu enhancer could be the boundary for CSR-associated somatic mutations. We propose that the core E mu enhancer plays a central role in the temporal dissociation of somatic hypermutation from class switching

Equity of accessibility to dialysis facilities.

International audiencePatients' end-stage renal disease (ESRD) characteristics are changing. Improving the quality of care requires a steady adaptation of treatment modalities together with equity of access to dialysis facilities. We explored the ability of the health system to cope with the demand of ESRD care. An analysis of a 5-year follow-up cohort of ESRD patients in the Limousin region, France, was performed. Data were entered in the Multi-Source Information System of the Renal Epidemiology and Information Network (REIN). The participation rate of centres was complete. We analysed patient characteristics, therapeutic options and driving time to reach dialysis facilities. We investigated geographic accessibility by defining areas within 45 minutes from dialysis units. We constructed scenarios to assess the impact of health care reorganization. In-centre haemodialysis units represented 73% of treatment modalities. One quarter of patients lived at more than 45 minutes of their dialysis unit. Based on a scenario of creating an additional In-centre unit, the number of patients living far from their centre would decrease by 31%. This study emphasizes important issues related to ESRD epidemiology, comorbidity and health care planning. It stimulates the development of new scenarios allowing the assessment of equity in accessing health care facilities

Nephrol Dial Transplant

BACKGROUND: Recent evidence suggests overestimation of benefits associated with arteriovenous (AV) fistula versus graft in certain populations. We assessed hazards of all-cause and cause-specific hospitalization and death associated with AV access type in patients who started hemodialysis with a catheter in France, overall and by subgroups of age, sex, and comorbidities. METHODS: From the REIN Registry, we included patients who initiated hemodialysis with a catheter from 2010 through 2018, and identified first-created fistula or graft through the French national health-administrative database. We used joint frailty models to deal with recurrent hospitalizations and potential informative censoring by death, and inverse probability weighting to account for confounding. RESULTS: From the 18 800 patients included (mean age 68 ± 15 years, 35% women), 5% underwent AV graft creation first. Weighted hazard ratio (wHR) of all-cause hospitalization associated with graft was 1.08 (95% CI 1.02 to 1.15), that of vascular access-related hospitalization was 1.43 (95% CI 1.32 to 1.55), and those of cardiovascular- and infection-related hospitalizations were 1.14 (95% CI 1.03 to 1.26) and 1.11 (95% CI 0.97 to 1.28), respectively. Results were consistent for most subgroups, except that the highest hazard of all-cause, cardiovascular-, and infection- related hospitalizations with graft was blunted in patients with comorbidities (i.e. diabetes, wHR 1.01, 95% CI 0.93 -1.10; 1.10, 95% CI 0.96 to 1.26; and 0.94, 95% CI 0.78 to 1.12, respectively). CONCLUSIONS: In patients starting hemodialysis with a catheter, AV graft creation is associated with increased hazard of vascular access-related hospitalizations compared to fistula. This may not be the case for death or other causes of hospitalization

Granzyme B-secreting B cells as a potential cell therapeutic

International audienceB cells secreting granzyme B (GZMB+) with suppressive properties have been discovered in a growing number of immunological contexts, autoimmunity, chronic infection, and neoplasias, as well as in healthy volunteers under physiological conditions.To date, no phenotype has been proposed for these GZMB+ B cells, and their biology also remains uncharacterized.These data provide new insights into GZMB+ B cell biology and function that emerge as one component of a complex regulatory network. Successfully expanding these cells while maintaining their potent immunosuppressive properties provides new clues for novel future cell therapies

Vers une extension du registre REIN aux patients avec une maladie rénale chronique au stade 5 non traités par dialyse ou greffe ? Étude pilote

International audienceTo date, it is important to know more about the population of CKD stage 5 patients in order to better understand the practices of access to renal replacement therapy (RRT) or conservative treatment and to anticipate future needs. In April 2015, at the instigation of the Scientific Committee of REIN, a working group was formed to reflect on the opportunity and feasibility of a data collection on these patients. Between September 2017 and March 2018, 21 participating centers included 390 patients over a period of at least one month. The data collected included the patient's living conditions, level of study, mode of referral, clinical data and the therapeutic project. The median age at baseline was 71.4years (IQR: 58.4-80.4), 39.9% were diabetic. The median eGFR was 12mL/min/1.73m2 (IQR: 9-14). At inclusion, 77% of the patients were already followed in nephrology, 11% had been referred by a general practitioner. For the majority of patients included (81%), there was a RRT project. In 10% of cases, there was a project of conservative care, in 5% of cases the project was not yet decided and in 7% the project had not been yet discussed. At the latest news (median time 4.0months), 35% of patients were dialyzed, 9 (2%) have been pre-emptively transplanted, 25 (6%) died, 210 (54%) were still with a CKD stage 5. Our pilot study has shown the feasibility and interest of setting up such a data collection. Such a registry will provide important public health information regarding the demographic of nephrologists and advanced practices nurses. At the local level, this information will help the department to organize themselves to set-up pre-RRT information, implementation of care pathway nurses and multidisciplinary meetings for difficult cases. However, our pilot study shows that to ensure the completeness of the collection, the tracking upstream or downstream of nephrology consultations for eligible patients is essential and therefore requires dedicated human time on site